1. Field of the Invention
The present invention relates to processes for preparing enantiomerically enriched glycerol carbonate and to certain derivatives thereof which are useful as starting materials and intermediates in the synthesis of enantiomerically pure therapeutic agents, particularly .beta.-adrenergic blockers.
2. Statement of Related Art
Many therapeutic compounds are chiral, existing in right-handed (R), and left-handed (S) molecular forms known as enantiomers. Paired enantiomers have different optical activity in that they rotate polarized light in opposite directions; otherwise, they have identical physical properties. The molecular chirality which is characteristic of enantiomers is often due to the presence of an asymmetric carbon, i.e., a carbon atom bonded to four different substituent groups. Generally, the synthesis of compounds possessing an asymmetric center yield a racemate, unless optically active starting materials are used. Although certain therapeutic compounds exist as enantiomers, in many cases they are marketed as a mixture of equal quantities of paired enantiomers, known as a racemate. The therapeutic effect of each member of an enantiomeric pair may differ substantially, however, even though their structures are virtually identical. Recently, concern has arisen that therapeutic agents used in the form of racemates can create health problems, for example, when only one enantiomer is therapeutically effective, whereas the other is inactive, or works to counteract the desired therapeutic effect, or, in some cases, produces undesired side effects. Thus, there is considerable interest among drug manufacturers in making only the enantiomerically pure therapeutic agents.
One such class of therapeutically-active enantiomers is known as the .beta.-adrenergic blockers, or simply .beta.-blockers. These compounds are often used in clinical practice in the form of the racemate, although higher activity is exhibited by the S isomer in comparison with the R isomer. T. Walle et al., Biochem. Pharmacol., 37, 115 (1988).
Over the past decade, the use of hydrolytic enzymes has been proposed to effect resolution of chiral compounds in order to provide enantiomerically pure starting materials for the production of therapeutically-active enantiomers. See, for example, Cesti et al., U.S. Pat. No. 4,933,290 and Whitesides et al., U.S. Pat. No. 4,732,853. In use, however, the enantiomerically enriched starting materials heretofore proposed have certain inherent shortcomings. Glycidol derivatives, for example, are both thermally and chemically unstable. In addition, there are potential health hazards associated with their use.
It would be desirable to develop alternative methods for efficient and effective production of optically active starting materials and/or intermediates which are useful in the preparation of enantiomerically pure therapeutic agents, such as .beta.-adrenergic blockers, and which avoid the above-noted shortcomings of the prior art. Preparation of R and S glycerol carbonate can be accomplished by degradation of sugar derivatives but the method is lengthy and suffers from poor yields.
Insofar as is known, the preparation of an enantiomerically enriched glycerol carbonate via enzymatic methods has not previously been performed successfully. Hamaguchi et al., J. Agric. Biol. Chem., 49:1511 (1985).